The present invention, in some embodiments thereof, relates to medical devices and, more particularly, but not exclusively, to controlled delivery of therapeutic agents, in humans and in animal species.
Presently, most medications are consumed via several routes, mainly orally. Oral ingestion of most drugs is followed by inactivation of a large portion of those drugs while passing through the liver, and the rest of the drugs enter the blood stream in a surge, with diminishing activity over time as a result of excretion and metabolism. To maintain a constant drug level within the blood, there is a need for repeated oral ingestions.
Presently, there are 3 main non-invasive routes for drug administration: oral ingestion (e.g., tablets, fluids, powder), cutaneous absorption (e.g., patches, creams), and trans-mucosal diffusion, for example, via lungs (inhalation), via rectum (suppositories), via vagina (e.g., tablets, creams, pessaries), and other locations (e.g., ears, nose, eyes).
Though oral ingestion of drugs is the most prevalent method for drug administration, there are several reasons why some drugs need a different route:                to bring the lowest needed dose of the active molecule as close as possible to the target organ with minimal or no influence on other parts of the body;        to refrain from some adverse events related to the alimentary tract (e.g. ingestion of aspirin and its derivatives that may adversely affect the stomach);        to avoid the loss of some of the drug while passing from the bowl to the blood stream (hepatic first pass metabolism);        to prevent drug related complaints which are usually due to the immediate elevation (surge) of drug's plasma levels;        to obtain a continuously low level of drug within the plasma, acting continuously on a target organ, without peaks which may allow for the use of very low amounts of drug which is not always possible with oral administration;        ongoing reluctance of many people to ingestion of many drugs, in the face of the growing need for administration of several medications at the same time; inability of some people to swallow oral medications.        
As mentioned above, mucosal routes for drug administration are promising, among them the vaginal route. The vagina has unique features for drug absorption which can be exploited in order to achieve desirable therapeutic effects. The vagina is a hollow organ with 3 planes. Its dimensions (length and diameter) vary between different women. Most of a vaginal surface is covered with stratified squamous epithelium without glands, nonetheless, it secretes large amounts of fluid. Some of the fluid comes from cervical secretions, and some is a transudate from the very rich vascular plexus around it. The uppermost part of the vagina contains goblet cells which secrete mucous; hence this part acts as a mucous membrane, being able to absorb medications in a somewhat different manner. These secretions play a large role in the absorption mechanism as they allow some of a drug to mix with the fluid (hence larger absorption surface) and it also maintains the proper pH for better absorption.
An important feature of the vagina is the huge vascular plexus surrounding it. The venous drainage of the vagina, mainly of its uppermost part, is very tortuous and empties into two different venous systems, thus drugs absorbed from the vaginal epithelium may escape first-pass hepatic metabolism. Due to the abundance of blood vessels, mainly at the upper part of the vagina, there is a transport of chemicals from draining veins into the arteries that lead into the uterus. This gives rise to the existence of “first uterine pass” theory, suggesting that medications absorbed from the deep part of the vagina will act on the uterus first, prior to any action anywhere else in the body.
The administration of a drug substance may be effected to induce either a local or systemic effect. Local therapies are usually aimed at treating infections of various kinds, and vaginal atrophy. Vaginal administration for systemic therapies takes advantage of the highly vascularized vaginal tissue without hepatic first pass metabolism, hence the need for much lower doses in order to achieve therapeutic serum concentration. The systemic absorption of the drug requires a number of well known steps—release from the delivery system, drug dissolution in vaginal fluid, and absorption across vaginal epithelium.
The vagina is surrounded by various organs, which may be treated vaginally as well as by oral ingestion. The bladder and the urethra are situated anterior to the vagina. The uterus and its cervix are located at the top of the vagina, and the recto-sigmoid is next to the posterior wall of the vagina.
Current medical treatments performed through the vagina may belong to one or more of the following 3 categories:                1. Local reactants—function on vaginal wall only, with minimal, if any, absorption beyond vaginal walls. Such medications are usually intended to treat infections, vaginal atrophy, or serve as a spermicide. These medications may belong to one of the following two groups:                    conventional drug delivery systems, marketed as creams and gels, vaginal tablets, pessaries and foams; and            modified release formulations which may be distributed as films and gels.                        2. Systemic reactants—destined to be absorbed systemically and affect distant organs. These medications, which are regarded as “modified release formulations” may appear as films and rings.        3. Surrounding organ reactants—destined to be absorbed beyond vaginal wall and affect neighboring organs, such as the uterus or the urinary bladder. These medications also belong to the “modified release formulation” and appear as films or rings.        
Local reactants are destined to function on vaginal wall or in close proximity. Most of the known drug delivery systems to the vagina have severe drawbacks such as leakage of the drug (as with creams, gels, and melted pessaries), limited residence time of the formulation on the vaginal wall due to gravity, motion, and poor adherence capacity of the drug or its carrier, the presence of menstrual cycle, local irritation by some of the drug carriers (tablets or pessaries), and personal care habits. In some cases, the vaginal normal flora, mainly the Lactobacillus Acidophilus, may be damaged, giving rise to abnormal flora. Some of these medications are designed be inserted manually by the user, a procedure not always welcome by all women. The affect of the drug is usually during a short period, and there is no way to stop it once applied into the vagina. Also, only a relatively small number of medications may be utilized by this route, without the ability to target a specific vaginal wall or adjacent organ.
Reactants destined to be absorbed systemically or function on adjacent organs such as the uterus or the bladder, are usually attached to a specific carrier that provides unique capabilities according to needs, such as the ability to supply the reactants in high doses, constant availability and constant touch with the vaginal mucosa.
Reference is now made to FIG. 1 which is a schematic illustration that pictorially shows a carrier used for controlled release of drugs via the vaginal mucosa. This carrier is a flexible ring, made of flexible polymers such as silicones, ethylene vinyl acetate (EVA), or styrene butandiene block copolymer. These rings are designed to release drugs in a controlled fashion after insertion into the vagina. Advantages of such a drug carrier are that it is user controlled, it is not messy, and it releases the drug constantly, hence there is no need for daily ingestion of medication. In most cases, ring carriers have a diameter of 50-55 millimeters and a cross sectional width of 4-9 millimeters. Drugs are contained within the ring either homogeneously dispersed within the polymer, or as a reservoir or a sandwich from which the drugs are absorbed into the mucosa.
After insertion into the vagina, the drug is released from the polymer into the vaginal fluid, from which it is further absorbed by various mechanisms into the sub-mucosal layers, and deeper into the blood stream.
The ring has several disadvantages as a carrier for drug release. Among them is the need to insert it manually, having to insert fingers into the vagina, and remove it in the same manner, with a finger. As a ring, it is impossible to direct the drug towards a specific organ, such as the bladder or uterus, hence the inability to affect a specific pelvic organ. Also, as a solid ring it is difficult to supply various drugs on the same carrier. This problem of variable drug administration in a ring has a proposed solution in U.S. Pat. No. 6,436,428 (Mahashabde, et. al.) which describes a way to place a drug within a ring by drilling several bores along the ring in order to contain a second drug. This complicated method may allow for more than one drug to be incorporated into a ring controlled release drug carrier.